Molecular Cytogenetic Analysis of Prostatic Adenocarcinomas from Screening Studies

Abstract

No objective parameters have been found so far that can predict the biological behavior of early stages of prostatic cancer, which are encountered frequently nowadays due to surveillance and screening programs. We have applied comparative genomic hybridization to routinely processed, paraffin-embedded radical prostatectomy specimens derived from patients who participated in the European Randomized Study of Screening for Prostate Cancer. We defined a panel consisting of 36 early cancer specimens: 13 small (total tumor volume (Tv) < 0.5 ml) carcinomas and 23 intermediate (Tv between 0.5-1.0 ml) tumors. These samples were compared with a set of 16 locally advanced, large (Tv > 2.0 ml) tumor samples, not derived from the European Randomized Study of Screening for Prostate Cancer. Chromosome arms that frequently (ie, > or = 15%) showed loss in the small tumors included 13q (31%), 6q (23%), and Y (15%), whereas frequent (ie, > or = 15%) gain was seen of 20q (15%). In the intermediate cancers, loss was detected of 8p (35%), 16q (30%), 5q (26%), Y (22%), 6q, and 18q (both 17%). No consistent gains were found in this group. In the large tumors, loss was seen of 13q (69%), 8p (50%), 5q, 6q (both 31%), and Y (15%). Gains were observed of 8q (37%), 3q (25%), 7p, 7q, 9q, and Xq (all 19%). Comparison of these early, localized tumors with large adenocarcinomas showed a significant increase in the number of aberrant chromosomes per case (Rs = 0.36, P = 0.009). The same was true for the number of lost or gained chromosomes per case (Rs = 0.27, P: = 0.05; Rs = 0.48, respectively; P < 0.001). Interestingly, chromosomal alterations that were found in previous studies to be potential biomarkers for tumor aggressiveness, ie, gain of 7pq and/or 8q, were already distinguished in the small and intermediate cancers. In conclusion, our data show that chromosomal losses, more specifically of 6q and 13q, are early events in prostatic tumorigenesis, whereas chromosomal gains, especially of 8q, appear to be late events in prostatic tumor development. Finally, early localized tumors, as detected by screening programs, harbor cancers with aggressive genetic characteristics.

Expression analysis of imbalanced genes in prostate carcinoma using tissue microarrays

“…The c-myc gene is located on chromosome 8q, the gain of which is an early event in prostate carcinogenesis (Alers et al, 2001). Amplification of the c-myc locus 8q24 is linked to higher Gleason scores (Qian et al, 2002) and a poor prognosis (Sato et al, 1999;Tsuchiya et al, 2002).…”

“…To reveal the most abundant chromosomal imbalances detected in prostate carcinoma, we performed an exhaustive search of six CGH studies, including a total of 145 primary prostate cancers (Sattler et al, 1999;Alers et al, 2001;Verdorfer et al, 2001;Zitzelsberger et al, 2001;Steiner et al, 2002;Wolter et al, 2002;Paris et al, 2003) as well as one array CGH study of 16 primary prostate cancers (Paris et al, 2003). In order to identify candidate genes that may be directly affected by these chromosomal imbalances, we screened a list of the top 250 most up-regulated and down-regulated genes as revealed by a recent meta-analysis of four independent expression microarrays including 61 prostate cancer samples (Rhodes et al, 2002).…”

“…In prostate carcinoma, several of these imbalances were shown to correlate with prostate cancer progression. For example, gains of chromosomes 7 and 8q were found to increase with tumour stage and grade (Alers et al, 2001). However, owing to the large size of imbalanced chromosomal regions, the group of genes to be considered as possible candidates is usually in the range of several hundreds.…”

“…First, an exhaustive search for imbalanced chromosomal regions from seven CGH and array CGH studies was performed (Sattler et al, 1999;Alers et al, 2001;Verdorfer et al, 2001;Zitzelsberger et al, 2001;Steiner et al, 2002;Wolter et al, 2002;Paris et al, 2003). Next, the results were compared to a recent meta-analysis of four independent expression array data sets (Rhodes et al, 2002) in order to define candidate genes located within regions recurrently changed in copy number.…”

LIM Kinase 1 Is Essential for the Invasive Growth of Prostate Epithelial Cells

“…These results suggest that a reduction in LIMK1 concentration induced changes in the actin cytoskeleton reorganization, the adhesion pattern, and localization of MT1-MMP in PC3 cells. prostatic adenocarcinomas indicated a gradual increase for the number of patients with gain of chromosome 7pq with increasing tumor volume (45). Importantly, these chromosomal alterations are also found in primary tumors that showed progression after radical prostatectomy (46), suggesting a possible correlation of LIMK1 expression as a biomarker for prostate cancer progression.…”